Vasoactive intestinal peptide (VIP) is a bronchorelaxant which is absent from or present only at relatively low levels in the lungs of asthmatics, but present in lungs of nonasthmatics. See Ollerenshaw et al., N. Engl. J. Med., 320, 1244-1248 (1989). This implies that VIP is a factor in normal lung function and that its depletion may play a causal role in the pathogenesis of asthma. VIP is degraded by tryptase, a serine protease which is found in large quantities in mast cells and is released upon mast cell degranulation. See Tam and Caughey, Am. J. Respir. Cell Mol. Biol., 3, 27-32 (1990); and Wenzel et al., Am. Rev. Respir. Dis., 137, 1002-1008 (1988). Thus, it has been hypothesized that if tryptase action in the lung could be inhibited, VIP levels would be higher than if the action of tryptase were not inhibited. Tryptase inhibition logically provides a method of treatment for mast-cell mediated diseases, e.g., asthma.
The activities of extracellular proteases are usually tightly controlled through the secretion of protein-based inhibitors. See Travis et al., Ann. Rev. Biochem., 52, 655-709 (1983). No biological inhibitors for tryptase have been disclosed in the literature to date. Many known serine protease inhibitors, including secretory leukocyte protease inhibitor (SLPI, also known as human seminal inhibitor-I (HUSI-I) and antileukoprotease-1 (ALP-1)) have been tested as tryptase inhibitors. See Smith et al., J. Biol. Chem., 259, 11046-11051 (1984); Hochstrasser et al., Eur. Arch. Otorhinolaryngol., 249, 455-458 (1993); and Alter et al., Arch. Biochem. and Biophys., 276, 26-31 (1990). Little or no tryptase inhibitory activity has been reported, however.
It would be desirable to have tryptase inhibitors, a procedure for identifying such inhibitors, and means for treating mast cell- and/or tryptase-related disorders. Such advances in the art are the subject of the present invention.